1. Field of the Invention
The present invention relates to mass spectrometers and methods of mass spectrometry.
2. Discussion of the Prior Art
Various types of mass spectrometers are known which use a mass analyser which incorporates a time to digital converter (“TDC”) also known as an ion arrival counter. Time to digital converters are used, for example, in time of flight mass analysers wherein packets of ions are ejected into a field-free drift region with essentially the same kinetic energy. In the drift region, ions with different mass-to-charge ratios in each packet of ions travel with different velocities and therefore arrive at an ion detector disposed at the exit of the drift region at different times. Measurement of the ion transit-time therefore determines the mass-to-charge ratio of that particular ion.
Currently, one of the most commonly employed ion detectors in time of flight mass spectrometers is a single ion counting detector in which an ion impacting a detecting surface produces a pulse of electrons by means of, for example, an electron multiplier. The pulse of electrons is typically amplified by an amplifier and a resultant electrical signal is produced. The electrical signal produced by the amplifier is used to determine the transit time of the ion which struck the detector by means of a time to digital converter which is started once a packet of ions is first accelerated into the drift region. The ion detector and associated circuitry is therefore able to detect a single ion impacting onto the detector.
However, such ion detectors exhibit a certain dead-time following an ion impact during which time the detector cannot respond to another ion impact. A typical detector dead time may be of the order of 1-5 ns. If during acquisition of a mass spectrum ions arrive during the detector dead-time then they will consequently fail to be detected, and this will have a distorting effect on the resultant mass spectra.
It is known to use dead time correction software to correct for distortions in mass spectra. However, software correction techniques are only able to provide a limited degree of correction. Even after the application of dead time correction software, ion signals resulting in more than one ion arrival on average per pushout event at a given mass to charge value will result in saturation of the ion detector and hence result in a non-linear response and inaccurate mass determination.
This problem is particularly accentuated with gas chromatography and similar mass spectrometry applications because of the narrow chromatographic peaks which are typically presented to the mass spectrometer which may be, for example, 2 seconds wide at the base.
Known time of flight mass spectrometers therefore suffer from a limited dynamic range especially in certain particular applications.
It is therefore desired to provide an improved mass spectrometer and methods of mass spectrometry.
The mass spectrometer according to the preferred embodiment enables the dynamic range of the detector to be extended. In particular, it is possible to alternate between two or more sensitivity ranges during an acquisition. One range is tuned to have a high sensitivity. A second range is adjusted to be at a lower sensitivity than the first range by a factor of up to ×100. Preferably, the difference in sensitivity between the first and second sensitivity modes is at least a factor ×10, ×20, ×30, ×40, ×50, ×60, ×70, ×80, ×90 or ×100.
Exact mass measurements can be made using a single point lock mass common to both high and low sensitivity ranges.
Although in the preferred embodiment the sensitivity is changed by the operation of a z-lens, other embodiments are also contemplated wherein in a more general arrangement, the ion optical system between the ion source and the mass analyser is altered or changed so that ions passing therethrough are focused/defocused thereby altering the ion transmission efficiency. It is possible to change the ion transmission efficiency by a number of methods, including: (i) altering a y-focusing lens, which may be an Einzel lens; (ii) altering a z-focusing lens, which may be an Einzel lens; (iii) using a stigmatic focusing lens, preferably having a circular aperture, which focuses/defocuses an ion beam in both the y- and z-directions; and (iv) using a dc quadrupole lens which can focus/defocus in the y-direction and/or the z-direction as desired.
Utilising z-focusing is preferred to other ways of altering the ion transmission efficiency since it has been found to minimise any change in resolution, mass position and spectral skew which otherwise seem to be associated with focusing/deflecting the ion beam in the y-direction. However, in less preferred embodiments the ion beam may be altered in the y-direction either instead of the z-direction or in addition to the z-direction.
At least an order of magnitude increase in the dynamic range can be achieved with the preferred embodiment. It has been demonstrated that the dynamic range can be extended from about 3.25 orders of magnitude to about 4.25 orders of magnitude with a GC (gas chromatography) peak width of about 1.5s at half height.
Preferably, the ion source is a continuous ion source. Further preferably, the ion source is selected from the group comprising: (i) an electron impact (“EI”) ion source; (ii) a chemical ionisation (“CI”) ion source; and (iii) a field ionisation (“FI”) ion source. All these ion sources may be coupled to a gas chromatography (GC) source. Alternatively, and particularly when using a liquid chromatography (LC) source either an electrospray or an atmospheric pressure chemical ionisation (“APCI”) ion source may be used.
Preferably, the mass analyser comprises a time to digital converter.
Preferably, the mass analyser is selected from the group comprising: (i) a quadrupole mass analyser; (ii) a magnetic sector mass analyser; (iii) an ion trap mass analyser; and (iv) a time of flight mass analyser, preferably an orthogonal acceleration time of flight mass analyser.
Preferably, the mass spectrometer further comprises control means arranged to alternately or otherwise regularly switch the z-lens, or more generally the ion optics, back and forth between at least first and second modes. In this embodiment, two data streams are stored as two discrete functions presenting two discrete data sets. Once the ratio of the high sensitivity to low sensitivity data has been determined, the data can be used to yield linear quantitative calibration curves over four orders of magnitude. Furthermore, the system can be arranged so that exact mass data can be extracted from either trace. Therefore, if a particular eluent produces a mass spectral peak which is saturated in the high sensitivity data set and therefore exhibits poor mass measurement accuracy, the same mass spectral peak may be unsaturated and correctly mass measured in the lower sensitivity trace. By using a combination of both traces, as a sample elutes exact mass measurements may be produced over a wide range of sample concentration.
The relative dwell times in the high and low sensitivity modes may either be the same, or in one embodiment more time may be spent in the higher sensitivity mode than in the lower sensitivity mode. For example, the relative time spent in a high sensitivity mode compared with a low sensitivity mode may be at least 50:50, 60:40, 70:30, 80:20, or 90:10. In other words, at least 50%, 60%, 70%, 80% or 90% of the time may be spent in the higher sensitivity mode compared with the lower sensitivity mode.
Alternatively, the control means may be arranged to switch the z-lens, or more generally the ion optics, from the first mode to the second mode when the detector is approaching or experiencing saturation and/or to switch the z-lens, or more generally the ion optics, from the second mode to the first mode when a higher sensitivity is possible without the detector substantially saturating in the first mode. According to the preferred embodiment, low mass peaks may be ignored in the determination of whether or not to switch sensitivities and in one embodiment it is only if mass peaks falling within a specific mass to charge range (e.g. m/z≧50, or 75, or 100) saturate or approach saturation that the control means switches sensitivity modes. Additionally/alternatively to ignoring saturation of low mass peaks and concentrating on mass peaks in one or more specific mass ranges (which are preferably predefined, but in less preferred embodiments do not necessarily need to be), the control means may switch sensitivity modes based upon whether specific, preferably predetermined, mass peaks are approaching saturation or are saturated, or if an improved mass spectrum including that specific mass peak could be obtained by switching to a different sensitivity mode.
Preferably, the mass spectrometer further comprises a power supply capable of supplying from −100 to +100V dc to the z-lens. In one embodiment, the z-lens may be a three part Einzel lens wherein the front and rear electrodes are maintained at substantially the same dc voltage, e.g. for positive ions around −40V dc, and an intermediate electrode may be varied, for positive ions, from approximately −100V dc in the high sensitivity (focusing) mode anywhere up to approximately +100V dc in the low sensitivity (defocusing) mode. For example, in the low sensitivity mode a voltage of −50V dc, +0V dc, +25V dc, +50V dc or +100V dc may be applied to the central electrode.
Preferably, when the z-lens defocuses a beam of ions passing through the z-lens, the beam of ions is diverged to have a profile or area which substantially exceeds the profile or area of an entrance aperture to the mass analyser by at least a factor ×2, ×4, ×10, ×25, ×50, ×75, or ×100.
Preferably, in the first mode at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or substantially 100% of the ions are arranged to pass through the entrance aperture.
Preferably, in the second mode less than or equal to 15%, 10%, 5%, 4%, 3%, 2%, or 1% of the ions are arranged to pass through the entrance aperture.
According to one embodiment, the ion optical system is arranged and adapted to be operated in at least three different sensitivity modes. In yet further embodiments four, five, six etc. up to practically an indefinite number of sensitivity modes may be provided.